The technical field of this invention is the treatment of movement disorders by implanting in preselected brain sites devices which focally release neuroinhibitory compounds. Candidate movement disorders for this treatment include Parkinson's disease, Huntington's chorea, and epilepsy.
Neuroinhibitory compounds include the inhibitory neurotransmitters gamma amino-butyric acid (GABA) and in some cases dopamine. Neurotransmitters are small molecules (less than 1 kilodalton (kD) molecular weight) which act as chemical means of communication between neurons. They are synthesized by the presynaptic neuron and released into the synaptic space where they then act on receptors specific for that particular neurotransmitter on postsynaptic neurons. GABA is considered a general inhibitory neurotransmitter, since receptors for GABA have been identified in every brain region studied to date (Krnjevic, K., 1991, IN: GABA Mechanisms in Epilepsy, Wiley-Liss, pp. 47-87).
Paralysis agitans, more commonly known as Parkinson's disease, is characterized by a lack of the neurotransmitter, dopamine, within the striatum of the brain, secondary to the destruction of the dopamine secreting cells of the substantia nigra. The loss of these dopamine secreting cells disrupts the normal activity pattern of certain neural pathways through the basal ganglia to the thalamus. It is postulated that one result of these alterations in basal ganglia activity is an increase in the activity of certain neurons inhibitory to the thalamus, thereby decreasing excitatory stimulus from the thalamus to the motor cortex. For normal movement, excitatory thalamic signals are required to modulate signals from the motor cortex to the muscles of the body. Subjects with parkinsonian symptoms display movement disorders including stiffness and slowness of movement and rhythmic tremor of limbs.
These clinical symptoms can be improved by the systemic administration of dopamine precursors such as levodopa (L-dopa) (Calne et al. (1969) Lancet ii:973-976), or dopamine agonists such as bromocriptine (Caine et al. (1974) Bri. Med. 3. 9:442-444) and (+)-4-propyl-9-hydroxynapthoxacine (de Yebenes et al. (1987) Movement Disorders 2:291-299), all of which are able to cross the blood-brain barrier. Dopamine, itself, cannot be administered systemically because of its inability to cross the blood-brain barrier. It has been discovered and disclosed in U.S. Pat. No. 4,892,538 that localized delivery of dopamine to the striatum can alleviate certain parkinsonian movement disorders.
As an adjunct or alternative to dopamine therapy, treatment with the inhibitory neurotransmitter GABA has been considered. Postmortem brain studies have shown that patients with Parkinson's disease have decreased basal ganglia GABA function in addition to dopamine deficiencies (Bennet, J. P., et al., 1987 Ann. Neurol. 21:41-45). Using experimental animal models for Parkinson's, GABA and its agonists have been administered through systemic or intraventricular routes, or by acute localized infusion to the basal ganglia (Bennet, J. P. et al. supra; Saji, M., et al. 1987 Science 235;66-69; Carvey, P. M. et al. 1991 Movement Disorders 6:272). As with similar types of dopamine therapy, the systemic or intraventricular application of GABA in human patients would likely lead to undesirable side effects because the inhibitory neurotransmitter would also affect GABA receptors in brain areas unrelated to the pathological condition. Localized infusion through cannulae of GABA-mimetic drugs would be inconvenient and would likely be associated with problems such as infection and mechanical failure of pumping devices.
Stereotaxic surgery, or the placement of precisely localized lesions in the brain has been practiced in some patients, and this procedure appears to provide some relief of parkinsonian symptoms in certain cases. The procedure is risky, however, and opinions among neurosurgeons differ as to the best way of making the lesion and what its ideal location should be. Lesions in various regions of the basal ganglia, for instance in the sub-thalamic nucleus (STN) and in the globus pallidus internus (GPi), have been tried with various levels of success in alleviating parkinsonian movement disorders. These locations (STN and GPi) were chosen for destruction based on the hypothesis that, in parkinsonian disorders, excessive activity (disinhibition) of neurons with cell bodies located in the STN and/or the GPi (see FIG. 1) leads to abnormal inhibition of thalamic neurons. The excitatory activity of thalamic projections to the motor cortex is required for normal movement. Thus, it was postulated that the success of lesions to the STN and the GPi was due to interruption of pathways leading to excessive inhibition of thalamic neurons. (For a review of this hypothesis, see Aebischer, P., et al., 1991, Science 252:133.) Lesioning of specific brain areas as therapy is problematic, however, because the lesion necessarily destroys all neurons in the selected area, including those that are functioning normally.
Huntington's chorea is a genetically transmitted disease characterized by the onset in middle age of choreiform movement disorders. One affected brain area in Huntington's disease, like Parkinson's disease, is thought to be the basal ganglia. In contrast to Parkinson's, however, the dopaminergic neurons of the substantia nigra are thought to be intact in Huntington's disease. In Huntington's, there is a generalized destruction of neurons having cell bodies in the striatum. This degeneration affects the output of the striatum to the GPe, the GPi and the SNpr, among others. Similar to Parkinson's disease, loss of striatal efferent connections to these nuclei results in a generalized disinhibition of the GPi and SNpr thalamic outputs. Treatment has generally been limited to tranquilizers, phenothiazines, and other drugs which act systemically and non-specifically to depress the central nervous system. It has been shown in a number of animal models that treatment with GABA can lead to amelioration diskenisia.
There exists a need for methods to correct malfunctioning pathways of the basal ganglia without causing excessive trauma. More specifically, there exists a need for methods to specifically inhibit the activity of neurons within preselected brain nuclei of the basal ganglia in order to alleviate movement disorders associated with Parkinson's and Huntington's diseases.
Epileptic seizures represent another form of movement disorder associated with neuronal over-activity. In contrast to Parkinson's disease and Huntington's chorea, however, the area of epileptic neuronal over-activity may be unique to each individual sufferer.
Seizures may originate in a temporal lobe, in other limbic structures, or in cortical areas that project to limbic areas, including frontal and occipital cortex. over-activity in basal ganglia, thalamic, and brainstem nuclei accompanies some clinical signs of focal seizure activity. Spread of over-activity often involves certain common structures such as the parahippocampal cortex, hippocampus, and amygdala. (Meldrum, B. S., 1990, The Lancet 336:231-234).
Standard treatment for epilepsy currently involves the chronic systemic administration of drugs which act as general central nervous system depressants, often with accompanying side-effects such as sedation and allergic reaction (Brodie, M. J., et al., 1990, The Lancet 336:425-426; Porter, R. J., 1990, The Lancet 336:423-424). Drug treatment for epilepsy during pregnancy and lactation presents special problems such as teratogenesis (three times the background rate) and neonatal sedation (Brodie, M. J., 1990, The Lancet 336:426-427).
An electrical implant ("neurocybernetic prosthesis") has been proposed as a method to prevent seizures by electrically interfering with neuronal signals (Lehrer, N. E., WO 85/01213, Mar. 28, 1985).
In severe cases, when seizures cannot be controlled by drugs, surgical removal of parts of the limbic system can sometimes break the neural circuit within which seizure activity becomes established, thereby decreasing seizure activity (Meldrum, B. S., supra). Clearly, removal of part of the brain is a treatment of last choice. What is needed is a method for the inhibition of neuronal over-activity in a specific epileptogenic area which would allow a neuroinhibitory drug to reach the desired area in an effective concentration, without causing undesirable side-effects.